2,3-dihydrothiopyran-4-ones as effective surrogates for
unreactive cis-dienes in Diels-Alder cycloaddition pro-
cesses.6 So far, a variety of synthetic procedures are
already available for the preparation of 2,3-dihydrothio-
pyran-4-ones, including (i) cycloaddition of structurally
appropriate acetylenic/divinyl ketones with hydrogen
sulfide,3,7 (ii) intramolecular Michael addition of thiolate
to an R,â-unsaturated carbonyl group,8 (iii) Diels-Alder
cycloadditions involving thiophosgene and donor-substi-
tuted thioaldehydes, respectively,9 (iv) conjugate addi-
tions to thiin-4-ones or oxidation of 4-thianones with
N-chlorosuccinimide (NCS),2b,4d,5e,f,6e and (v) dimsyl anion
mediated tandem fragmentation cyclization reactions of
R-alkenoyl cyclic ketene-(S,S)-acetals.10 However, some
of these methodologies suffer from low yields, lack of
generality to wide range of substrates, or formation of
regioisomers. To match the increasingly scientific and
practical demands for functionalized 2,3-dihydrothiopy-
ran-4-ones, it is still of continued interest and great
importance to explore novel and efficient synthetic ap-
proaches for such thia-heterocycles.
During the course of our studies on the chemistry of
R-oxo ketene-(S,S)-acetals,11 we have noted that R-alk-
enoyl ketene-(S,S)-acetals 1 show promising structural
feature as novel organic intermediates for (1) double
Michael acceptors serving as five-carbon 1,5-bielectro-
philic species, (2) dense and flexible substitution patterns,
and (3) good leaving alkylthio groups subjecting to a
nucleophilic vinyl substitution (SNV) reaction. Most
recently we developed a new synthetic strategy for the
construction of highly substituted six-membered car-
bocycles and aza-heterocycles, relying upon the utiliza-
tion of 1 as a five-carbon 1,5-bielectrophilic species in
formal [5C + 1C(N)] annulations with various carbon and
nitrogen nucleophilies, respectively.12 These results and
our continued interest in the development of new general
methods for biologically important heterocycles13 pro-
moted us to expand the formal [5 + 1] synthetic strategy
[5C + 1S] Annulation: A Facile and
Efficient Synthetic Route toward
Functionalized
2,3-Dihydrothiopyran-4-ones
Xihe Bi, Dewen Dong,* Yan Li, Qun Liu,* and
Qian Zhang
Department of Chemistry, Northeast Normal University,
Changchun 130024, P. R. China
Received September 28, 2005
A facile and efficient synthetic route toward highly substi-
tuted 2,3-dihydrothiopyran-4-ones 2 has been developed via
a formal [5C + 1S] annulation of readily available R-alkenoyl
ketene-(S,S)-acetals 1 with sodium sulfide nonahydrated salt
(Na2S‚9H2O) and utilized in the synthesis of 2-(4-chlorophen-
yl)-6-(morpholin-4-yl)-4H-thiopyran-4-one 5l, an inhibitor of
DNA-dependent protein kinase (DNA-PK).
In the past decades, thiopyrone derivatives including
types of thiin-4-ones, 4-thianones, and 2,3-dihydrothio-
pyran-4-ones have gained increasing attention for both
the interest of such heterocycles themselves and their
importance as key units in medicinal chemistry and
versatile intermediates in organic synthesis.1 Particu-
larly, 2,3-dihydrothiopyran-4-ones have been used in the
construction of analogues of natural products, such as
tetrahydrodicranenone B,2 pheromones,3 thromboxanes,4
and cyclopentanoids.5 Recently, Ward and co-workers
have utilized 4-O-silyloxy-2H-thiopyrans derived from the
(6) (a) Ward, D. E.; Gai, Y. Z.; Lai, Y. J. Synlett 1996, 261. (b) Ward,
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10.1021/jo052032g CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/24/2005
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J. Org. Chem. 2005, 70, 10886-10889